Dr. Keith Ferdinand from the Tulane University School of Medicine, Tulane Heart and Vascular Institute, New Orleans, LA moderated the topic "Heart Failure Treatment: A Focus on Treatment in Black Patients" with Drs. Christopher Leggett from the Cardiovascular Institute of Georgia at East Georgia Regional Medical Center, Statesboro, GA, Ileana Piña from the Montefiore Medical Center, New York, NY, and Frank Smart from the Louisiana State University School of Medicine, New Orleans, LA.

Dr. Leggett: I am Christopher J.W.B. Leggett, Director of Interventional Cardiology, Director of the Cardiac Catheterization Laboratory, and Director of the Cardiovascular Institute of Georgia at East Georgia Regional Medical Center.

Dr. Smart: I’m Frank W. Smart from the Louisiana State University School of Medicine, Professor and Chief of the Section of Cardiology, and Director of the Cardiovascular Center of Excellence.

Dr. Piña: I am Ileana Piña, Professor of Medicine, Epidemiology and Population Health at Einstein College of Medicine and Associate Chief of Cardiology for Academic Affairs at Montefiore-Einstein Medical Center.

DR. FERDINAND: Frank, I’m going to start with you. Give me a basic definition of heart failure (HF) and the risk factors for HF.
Dr. Smart: The basic definition, Keith, is when there’s not enough cardiac output to meet the metabolic needs of the body. That can manifest as poor function and poor exercise tolerance and congestion. The risk factors are those risk factors that we know for ischemic heart disease because ischemic heart disease, along with hypertension, is one of the classic problems causing HF.

Dr. Ferdinand: Okay, so that’s in the general population. We always talk about, although we don’t see them as often, certain rare forms of heart disease such as Chagas disease, which is a common condition in Mexico, Central and South America. With migration of persons from endemic areas, some of whom may have the disease and not know it, we have begun to see cases. In fact, as many as 300,000 people in the United States may have chronic Chagas disease.1-4

Dr. Smart: There is, as you said, a myriad of other things that are associated with HF. Actually, it’s now probably close to 200 different diagnoses related to HF so that HF is a syndrome and not really a diagnosis. There are dilated cardiomyopathies, infiltrated cardiomyopathies, and infectious cardiomyopathies. Those are all systolic HF. We’ve not even touched on HF with preserved ejection fraction with its multitude of causes. We are also realizing that HF of all types has a strong genetic preponderance and many single nucleotide polymorphisms have already been associated with various cardiomyopathies.

Dr. Ferdinand: I think for the purpose of this discussion, since you have appropriately suggested that HF can be quite complex, let’s focus mainly on systolic HF. Chris, in view of our focus mainly on systolic HF, can you give us some background on HF specifically in identified black patients or African Americans.

Dr. Leggett: Well, in the identified United States black patient population, there is a higher prevalence of HF nationally. When you focus primarily on systolic HF, in the majority, the number one cause remains coronary artery disease in the majority population. When you examine this issue from the standpoint of the prevalence of coronary disease and myocardial infarctions as a backdrop for causing systolic HF, black individuals are clearly disproportionately affected. African American women, when compared with white women, continue to carry the highest risk in the United States for having these conditions. However, beyond the spectrum of pure coronary disease, especially in African Americans, we should consider underlying hypertensive cardiovascular disease or poorly controlled hypertension as another major culprit that, over the years, leads to systolic HF. Once again, when we look at hypertensive patients, nationally and probably worldwide, blacks carry a much higher burden of hypertension and hypertensive cardiovascular disease than other groups.

Dr. Ferdinand: Now Chris, a point of controversy: Although in most of the classic landmark studies that are done related to HF and HF therapy, coronary disease is predominant in the majority population and clearly leads to HF, wouldn’t you agree, however, that in blacks HF may be more related to hypertension than coronary disease?

Dr. Leggett: I would agree that, because the prevalence of hypertension in the black patient subgroup population is so high worldwide, compared with any other racial/ethnic groups, it must be simultaneously considered as a leading cause for HF in blacks.

Dr. Ferdinand: Frank, when you look at HF—and we’re going to talk a little bit about various therapies, none in detail at this point but just as an overview—give us the basic approaches to patients who have symptomatic HF. Later, we’ll discuss whether these approaches have mortality benefit. So what do you use if a person presents with systolic HF?

Dr. Smart: There have been three drug classes that have been identified to make patients live longer and to some degree feel better, and two other drug classes that don’t really impact survival but do make patients feel better. The first, the mainstay of therapy are the angiotensin-converting enzyme (ACE) inhibitors and, in the absence of being able to tolerate them, the angiotensin receptor blockers (ARB). The second is a beta-blocker; in particular, three beta-blockers that have been shown to work in HF are carvedilol, bisoprolol, and metoprolol succinate. Finally, an aldosterone blocker, whether it’s eplerenone or spironolactone. The feel-better drugs are diuretics and digoxin in fairly low doses.

Dr. Ferdinand: Now the reason you use the term “feel better,” is because we don’t have actual mortality benefit with either diuretics or digoxin at this point?

Dr. Smart: Correct. There is no mortality benefit, but the Digitalis Investigation Group (DIG) trial5 and then the Randomized Assessment of Digoxin on Inhibitors of Angiotensin-Converting Enzyme (RADIANCE) trial6 and the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) trial7 all show that patients who were taking digoxin felt better and even exercised longer. Even patients with HF and preserved ejection fraction feel a little bit better with digoxin.

Dr. Ferdinand: Another controversial point would be if a patient was euvolemic; hence, we tend to stay away from the term congestive HF, where they have significant systolic dysfunction or history of HF with or without congestion. Can diuretics actually be harmful in those patients?

Dr. Smart: The point is far less contentious with HF physicians. Because of the fact that diuretics stimulate the renin-angiotensin system and the sympathetic nervous system, and cause electrolyte imbalances, we all recognize that diuretics may be harmful but are a necessary component to a treatment plan. As you mentioned a minute ago, however, if the patient is euvolemic, you should reduce or even stop the diuretics if you can.

Dr. Ferdinand: Chris, are there any clinical pearls that you would like to discuss before we specifically talk about the application of some of these pharmacologic management options in black patients?

Dr. Leggett: In general, I believe that the evidence-based proven therapies that we’ve prescribed to patients over the years still remain effective today. Overall, we find ourselves clinically complementing the basic cornerstones of HF therapy—ACE inhibitors, beta-blockers, and the diuretics—with additional medications that may provide some added symptomatic relief, as well as a possible survival benefit. These therapies continue to evolve.

Dr. Ferdinand: You know again, in most of the major HF trials, non-whites or self-identified blacks have, until recent years, been much under-represented and, indeed, I’ve practiced long enough to remember the Studies of Left Ventricular Dysfunction (SOLVD) trial8 in which there was a lack of either hospitalization or mortality benefit in the black cohort.9 Now in SOLVD, 12% were black; it may have been underpowered.10 There was also another study called the Beta-Blocker Evaluation of Survival Trial (BEST)11 with bucindolol, which was a National Heart, Lung, and Blood Institute–sponsored trial that did appear to have adequate sample size, and the black cohort did not appear to do as well with the trend toward an increased mortality with bucindolol versus the predominantly white population. We do understand that to the large extent these are very artificial terms when we talk about blacks, whites, and so on. I’ll ask Frank first: Is it disconcerting that we have the under-powering of some of these sub-populations in some landmark studies and then when we do get some of the studies, the data are not convincing?

Dr. Smart: I agree, many times we apply information from a large clinical trial to a population of patients not represented in that trial. Usually it is the application of the best information we have but we need to remember that certain patients were not represented and therefore may not share the same benefit as the overall study population. You don’t have to limit it to race; you could look at sex and age as well. If you were to look at older people, there really are very few data on people older than 80 with congestive HF, and yet the average age in the United States is 83 for HF patients.

Dr. Piña: Right, I think that we need to include a wide variety of patients, whether it’s by sex, ethnicity, or age. If you look at the ACE inhibitor trials and separate the women, the hazard ratio in women is not as impressive as it is in the men. Similarly with the black subjects in those studies, ACE inhibitors may not be as effective in that racial/ethnic group.
Now why aren’t we getting more women into trials? Well, we exclude women of childbearing age, so that excludes younger women. Also, if you look at the SOLVD trial, those patients were found, not because we had HF programs back then, but because we were trolling the echocardiography lab looking for HF and post–myocardial infarction patients who were, of course, primarily men. So, fewer women got into the trials. Women may also provide a greater challenge in that they rely more on consent from their families before they agree to participate in a clinical trial. Therefore, it may be advisable to include a family caregiver when attempting to enroll women in clinical trials.

Dr. Smart: The large randomized trial gives us the best information we have, but occasionally a sub-group analysis does not show the same benefit or risk as the entire study cohort. We usually believe this is due to a lack of prospective design and under-powering of the particular subgroup to answer the question with statistical certainty. We do know, however, from the bucindolol trial, that there is a genetic predisposition that determines whether or not bucindolol, as well as perhaps other beta blockers, will benefit. That has spurned what I think is the next wave in medicine, which is more of a personalized medicine approach using a patient’s genetics to design a treatment. The field of pharmacogenomics will help to decide what drugs people should get in the near future.

"African Americans, and in particular African American women … carry the highest risk in the United States for having [CAD, MI, and CV morbidity and mortality]. Unfortunately African Americans, Hispanics and women of all ethnicities suffer from a disparity in access to life saving technologies and pharmacologic therapies."Christopher Leggett, MD

"There is, as you said, a myriad of other things that are associated with HF. Actually, it’s now probably close to 200 different diagnoses related to HF so that HF is a syndrome and not really a diagnosis."Frank Smart, MD

"It is so hard to get patients to take so many pills … We have a responsibility to try to find a regimen that they are more likely to be adherent to by reviewing their medications at each visit and removing drugs that are not necessary, and engaging patients in their care."Ileana L. Piña, MD

"Although clinicians attempt to replicate dosages of the individual medications hydralazine and isosorbide dinitrate, the FDA has clearly indicated based upon pharmacokinetic studies, that there is no therapeutic substitute for the fixed-dose combination isosorbide dinitrate/ hydralazine."Keith C. Ferdinand, MD